Metabolic Reprogramming Drives a Refractory Mixed Th2/Th17 Endotype in Chronic Rhinosinusitis with Nasal Polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) exhibits significant endotypic heterogeneity. While Western populations predominantly display Type 2 (T2) inflammation, Asian cohorts, including those in China, show a high prevalence of mixed, non-T2, and neutrophilic endotypes. A subset of patients with a mixed Th2/Th17 profile often remains refractory to standard therapies.

We hypothesized that this mixed Th2/Th17 endotype is associated with distinct metabolic and structural alterations that differentiate it from purely T2-driven disease, and we aimed to characterize these features and their prognostic implications.

Integrated transcriptomic and metabolomic analyses were performed on nasal tissue from 103 subjects (78 CRSwNP and 25 controls). Patients were stratified into High-Th17 and Low-Th17 endotypes based on a specific gene signature. Immunometabolic profiles, barrier remodeling markers, and postoperative disease control rates were compared across endotypes.

Approximately 30.8% of CRSwNP patients were classified as High-Th17. These patients exhibited clinical features similar to Th2-dominant disease, including comparable elevations in serum IgE and blood eosinophils. However, prognostic differences emerged: patients with a mixed 'Double-High' profile (concurrent Th2/Th17 elevation) showed a higher disease control rate versus the 'Pure Th2' subgroup (48% vs 25%). Multi-omics integration revealed that the High-Th17 endotype was significantly associated with a shift toward aerobic glycolysis-like metabolism and accumulation of pro-inflammatory lipid mediators. This metabolic reprogramming strongly correlated with transcriptomic markers of squamous metaplasia and barrier hyper-keratinization, suggesting a transition from an edematous to a structurally remodeled tissue state.

The High-Th17 endotype in CRSwNP represents a mixed inflammatory state with clinical overlap with T2 disease but distinct biological trajectories. The observed association between mixed Th2/Th17 inflammation, enhanced glycolysis, and squamous metaplasia provides a potential molecular framework for understanding the recalcitrance of this subgroup, though further mechanistic validation is required.

Not applicable.